Unraveling the Metabolic and Microbiome Signatures in Fecal Samples of Pregnant Women with Prenatal Depression.

Background/Objectives: Prenatal depression (PND) poses a significant threat to the health of both the mother and the developing fetus. Despite its increasing prevalence, the pathophysiology of PND is not yet fully elucidated. Methods: In this study, we aimed to investigate the fecal metabolites and gut microbiota in PND patients compared to healthy controls and to explore potential correlations between these factors. Results: Through untargeted metabolomics analysis, we identified 75 significantly altered metabolites in PND patients, of which 27 were structurally annotated and implicated key pathways, such as linoleic acid metabolism and phenylalanine, tyrosine, and tryptophan biosynthesis. Notably, two Clostridia-associated enterobacteria, unclassified_c_Clostridia and unclassified_f_Lachnospiraceae, which were enriched in the PND group, were significantly positively correlated with tyrosine and negatively correlated with multiple sulfated neurosteroids. Conclusions: Our findings underscore a robust association between gut microbiota dysbiosis and metabolic disturbances in PND, with specific alterations noted in tyrosine metabolism, sulfated neurosteroid homeostasis, and linoleic acid pathways. These dysregulated metabolites-tyrosine, sulfated neurosteroids, and linoleic acid-may serve as potential diagnostic biomarkers and therapeutic targets. Moreover, their interplay provides new insights into the pathophysiological mechanisms of PND, particularly highlighting the role of gut-brain axis signaling in neuroendocrine dysregulation and inflammatory responses. However, further large-scale studies and animal models are required to validate these findings and explore detailed mechanistic pathways.